Optimizing (Longer, Deeper) Cooling for Neonatal Hypoxic-Ischemic Encephalopathy(HIE)

Optimizing Cooling Strategies at < 6 Hours of Age for Neonatal Hypoxic-Ischemic Encephalopathy

The Optimizing Cooling trial will compare four whole-body cooling treatments for infants born at 36 weeks gestational age or later with hypoxic-ischemic encephalopathy: (1) cooling for 72 hours to 33.5°C; (2) cooling for 120 hours to 33.5°C; (3) cooling for 72 hours to 32.0°C; and (4) cooling for 120 hours to 32.0°C. The objective of this study is to evaluate whether whole-body cooling initiated at less than 6 hours of age and continued for 120 hours and/or a depth at 32.0°C in will reduce death and disability at 18-22 months corrected age.

Study Overview

• Status: Terminated
• Conditions: Hypoxia, Brain; Hypoxia-Ischemia, Brain; Hypoxic-Ischemic Encephalopathy; Infant, Newborn; Ischemic-Hypoxic Encephalopathy; Encephalopathy, Hypoxic-Ischemic
• Intervention / Treatment: Procedure: Whole-body Cooling

Detailed Description

Hypoxic-ischemic encephalopathy (HIE) is a rare, but life-threatening condition characterized by brain injury due to asphyxia diagnosed at or shortly after birth. According to the World Health Organization, more than 722,000 children died from birth asphyxia and birth trauma worldwide in 2004. An estimated 50-75 percent of infants with severe (stage 3) HIE will die, with 55 percent of these deaths occurring in the first month. Up to 80 percent of infants who survive stage 3 HIE develop significant long-term disabilities, including intellectual disabilities, epilepsy, and cerebral palsy with hemiplegia, paraplegia, or quadriplegia; 10-20 percent develop moderately serious disabilities; and up to 10 percent are normal.

Previous studies have shown treatment with hypothermia to be an effective therapy for HIE. Currently, infants diagnosed with HIE at less than six hours of age are given whole-body cooling, decreasing their core body temperature to 33.5°C (93.2° Fahrenheit) for a period 72 hours using a cooling blanket. This treatment appears to protect the brain, decreasing the rate of death and disability and improving the chances of survival and neurodevelopmental outcomes at 18 months correct age. But additional trials are needed to help define the most effective cooling strategies.

The Optimizing Cooling trial will examine whether cooling for a longer time period and/or to a lower temperature will improve the chance of survival and neurodevelopmental outcomes at 18-22 months corrected age. Eligible infants with HIE will be placed in one of four cooling groups: (1) cooling for 72 hours to 33.5°C; (2) cooling for 120 hours to 33.5°C; (3) cooling for 72 hours to 32.0°C; and (4) cooling for 120 hours to 32.0°C. Infants will be monitored closely and receive the care of the Neonatal Intensive Care Unit (NICU).

Infants enrolled in the study will be placed on a cooling blanket - the same type of blanket children's hospitals use in the NICU, in operating rooms during surgeries, and to cool children with high fevers. Each infant will be cooled according to the study group he or she is assigned to. During cooling, the infant's temperature will be very closely monitored by continuous esophageal (core)temperature readings. This will be done by placing a soft, narrow, flexible plastic tube into the infant's nose and down to just above the stomach. Skin temperatures will also be monitored closely. At the end of the assigned period of cooling, the infant will be slowly re-warmed until a normal core temperature of 36.5 to 37.0°C (97.7 to 98.6°C) is reached.

Infants will be examined at 18-22 months corrected age to assess their neurodevelopmental outcomes.

Secondary Studies include:

A. Using aEEG to 1)predict mortality or moderate to severe disability at 18-22 months in term infants with HIE treated with systemic hypothermia and 2) to record electrical seizure activity to compare rewarming initiated at 72 hours and later rewarming that is initiated at 120 hours.

B. Secondary Study includes determining an association between MRI detectable injury and neurodevelopment at 18-22 months.

• Study Type: Interventional
• Enrollment (Actual): 364
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • California
    • Los Angeles, California, United States, 90025
      • University of California - Los Angeles
    • Palo Alto, California, United States, 94304
      • Stanford University
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
    • Durham, North Carolina, United States, 27705
      • RTI International
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Cincinnati Children's Medical Center
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University, Rainbow Babies and Children's Hospital
    • Columbus, Ohio, United States, 43205
      • Research Institute at Nationwide Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Univeristy of Pennsylvania
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Brown University, Women & Infants Hospital of Rhode Island
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center at Dallas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 6 hours (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Eligibility will be determined in a stepped process:

1. All infants with a gestational age ≥ 36 weeks will be screened for study entry if they are admitted to the NICU with a diagnosis of fetal acidosis, perinatal asphyxia, neonatal depression or encephalopathy.

2. Infants will be eligible if:

   • They have a pH ≤ 7.0 or a base deficit ≥ 16m mEq/ L on umbilical cord or any postnatal sample within 1 hour of age.
   • If, during this interval, they have a pH between 7.01 and 7.15, a base deficit is between 10 and 15.9 mEq/L, or a blood gas is not available, AND they have an acute perinatal event AND either a 10-minute Apgar score ≤ 5 or assisted ventilation initiated at birth and continued for at least 10 minutes.

3. Once these criteria are met, eligible infants will have a standardized neurological examination performed by a certified physician examiner. Infants will be candidates for the study when encephalopathy or seizures are present. For this study, encephalopathy is defined as the presence of 1 or more signs in 3 of the following 6 categories:

   • Level of consciousness: lethargy, stupor or coma;
   • Spontaneous activity: decreased, absent;
   • Posture: distal flexion, decerebrate;
   • tone: hypotonia, flaccid or hypertonia, rigid;
   • Primitive reflexes: a) suck, weak, absent; b) Moro, incomplete, flaccid;
   • Autonomic nervous system: a) pupils: constricted, unequal, skew deviation or non reactive to light; b) heart rate: bradycardia, variable heart rate or c) respiration: periodic breathing, apnea.

Eligible infants from multiple births will be enrolled in the same arm of the study.

Exclusion Criteria:

• Inability to randomize by 6 hours of age
• Major congenital abnormality
• Major chromosomal abnormality (including Trisomy 21),
• Severe growth restriction (≤ 1800gm birth weight),
• Infant is moribund and will not receive any further aggressive treatment,
• Refusal of consent by parent
• Refusal of consent by attending neonatologist
• Infants with a core temperature < 33.5°C for > 1 hour at the time of screening by the research team would not be eligible for the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 33.5°C for 72 hours; Target Temp: 33.5°C Duration: 72 hrs	Procedure: Whole-body Cooling; Whole-body cooling using a Blanketrol II or III to reach either a target core temperature of 33.5°C or 32.0°C for a duration of either 72 hours or 120 hours.; Other Names: Blanketrol II Model 222R; Blanketrol III Model 233 (used in the II mode)
Experimental: 33.5°C for 120 hours; Target Temp: 33.5°C Duration: 120 hrs	Procedure: Whole-body Cooling; Whole-body cooling using a Blanketrol II or III to reach either a target core temperature of 33.5°C or 32.0°C for a duration of either 72 hours or 120 hours.; Other Names: Blanketrol II Model 222R; Blanketrol III Model 233 (used in the II mode)
Experimental: 32.0°C for 72 hours; Target Temp: 32.0°C Duration: 72 hrs	Procedure: Whole-body Cooling; Whole-body cooling using a Blanketrol II or III to reach either a target core temperature of 33.5°C or 32.0°C for a duration of either 72 hours or 120 hours.; Other Names: Blanketrol II Model 222R; Blanketrol III Model 233 (used in the II mode)
Experimental: 32.0°C for 120 hours; Target Temp: 32.0°C Duration:120 hrs	Procedure: Whole-body Cooling; Whole-body cooling using a Blanketrol II or III to reach either a target core temperature of 33.5°C or 32.0°C for a duration of either 72 hours or 120 hours.; Other Names: Blanketrol II Model 222R; Blanketrol III Model 233 (used in the II mode)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death or Moderate to Severe Disability	Death includes any mortality prior to follow up at 18-22 months. Severe disability was defined by any of the following: a Bayley III cognitive score <70, a GMFCS level of 3-5, blindness or profound hearing loss (inability to understand commands despite amplification). Moderate disability was defined as a Bayley cognitive score of 70-84 and either a GMFCS level of 2, seizure disorder, or a hearing deficit requiring amplification to understand commands.	Birth to 22 months corrected age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death	Death includes any mortality prior to follow up at 18-22 months.	Birth to 22 months corrected age
Level of Disability Among Survivors	Among survivors number of normal infants and infants with mild, moderate, and severe disability Severe disability was defined by any of the following: a Bayley III cognitive score <70, a GMFCS level of 3-5, blindness or profound hearing loss (inability to understand commands despite amplification). Moderate disability was defined as a Bayley cognitive score of 70-84 and either a GMFCS level of 2, seizure disorder, or a hearing deficit requiring amplification to understand commands. Mild impairment was defined by a cognitive score 70-84, or a cognitive score ≥ 85 and any of the following: presence of a GMFCS level 1 or 2, seizure disorder or hearing loss not requiring amplification. Normal was defined by a cognitive score ≥ 85 in the absence of any neurosensory deficits or seizures after NICU discharge.	Follow up at 18-22 months corrected age
Withdrawal of Care	Number of infants for whom aggressive care is withdrawn	Birth through hospital discharge, average 22 days.
Clinical Neonatal Seizures	Documented seizures during hospital course	Through death, discharge, or transfer
Bayley Cognitive Score	Bayley Scale of Infant Development Composite Cognitive Score. The total composite score is reported, ranging from the lowest score of 55 to the highest score of 145. Lower values specify worse outcome.	Follow up at 18-22 months corrected age
Cerebral Palsy		Follow up at 18-22 months corrected age
Level of Disability Among Survivors, by Level of HIE	Among survivors, number of normal infants and infants with mild, moderate and severe disability Severe disability was defined by any of the following: a Bayley III cognitive score <70, a GMFCS level of 3-5, blindness or profound hearing loss (inability to understand commands despite amplification). Moderate disability was defined as a Bayley cognitive score of 70-84 and either a GMFCS level of 2, seizure disorder, or a hearing deficit requiring amplification to understand commands. Mild impairment was defined by a cognitive score 70-84, or a cognitive score ≥ 85 and any of the following: presence of a GMFCS level 1 or 2, seizure disorder or hearing loss not requiring amplification. Normal was defined by a cognitive score ≥ 85 in the absence of any neurosensory deficits or seizures after NICU discharge.	Follow up at 18-22 months corrected age
Visual Impairment	Visual impairment is defined as bilateral blindness with some/no useful vision	Follow up at 18-22 months corrected age
Hearing Impairment	Hearing impairment is defined as hearing impairment despite amplification	Follow up at 18-22 months corrected age
Multiple Disabilities	Multiple disabilities is defined as two or more of the following 5 components: disabling CP, GMFCS level 3-5, Bayley cognitive score < 70, blindness, or deafness.	Follow up at 18-22 months corrected age
Multiorgan Dysfunction	The data needed for this analysis are not collected directly, and will not be analyzed as the study was terminated early and no funds available to complete this complex analysis. The data for this study will be stored at the NICHD-DASH for investigators.	Until death, discharge, or transfer

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severe Neonatal Brain Abnormalities	The data for this analysis have not yet been collected. MRIs taken between 7-14 days will be examined.	7-14 days of life

Collaborators and Investigators

• Sponsor: NICHD Neonatal Research Network
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Center for Research Resources (NCRR)
• Investigators: Principal Investigator: Michele C Walsh, MD MS, Case Western Reserve University, Rainbow Babies and Children's Hospital; Principal Investigator: Carl D'Angio, MD, University of Rochester; Principal Investigator: Barbara Schmidt, MD, MSc, University of Pennsylvania

Publications and helpful links

General Publications

• Shankaran S. Outcomes of hypoxic-ischemic encephalopathy in neonates treated with hypothermia. Clin Perinatol. 2014 Mar;41(1):149-59. doi: 10.1016/j.clp.2013.10.008.
• Shukla VV, Bann CM, Ramani M, Ambalavanan N, Peralta-Carcelen M, Hintz SR, Higgins RD, Natarajan G, Laptook AR, Shankaran S, Carlo WA. Predictive Ability of 10-Minute Apgar Scores for Mortality and Neurodevelopmental Disability. Pediatrics. 2022 Apr 1;149(4):e2021054992. doi: 10.1542/peds.2021-054992.
• Chalak LF, Pappas A, Tan S, Das A, Sanchez PJ, Laptook AR, Van Meurs KP, Shankaran S, Bell EF, Davis AS, Heyne RJ, Pedroza C, Poindexter BB, Schibler K, Tyson JE, Ball MB, Bara R, Grisby C, Sokol GM, D'Angio CT, Hamrick SEG, Dysart KC, Cotten CM, Truog WE, Watterberg KL, Timan CJ, Garg M, Carlo WA, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Association Between Increased Seizures During Rewarming After Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy and Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up: A Nested Multisite Cohort Study. JAMA Neurol. 2021 Dec 1;78(12):1484-1493. doi: 10.1001/jamaneurol.2021.3723.
• Chalak LF, Pappas A, Tan S, Das A, Sanchez PJ, Laptook AR, Van Meurs KP, Shankaran S, Bell EF, Davis AS, Heyne RJ, Pedroza C, Poindexter BB, Schibler K, Tyson JE, Ball MB, Bara R, Grisby C, Sokol GM, D'Angio CT, Hamrick SEG, Dysart KC, Cotten CM, Truog WE, Watterberg KL, Timan CJ, Garg M, Carlo WA, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Association of Increased Seizures During Rewarming With Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up: A Nested Multisite Cohort Study. JAMA Neurol. 2021 Oct 18;78(12):1-10. doi: 10.1001/jamaneurol.2021.3723. Online ahead of print. Erratum In: JAMA Neurol. 2021 Dec 1;78(12):1533.
• Ambalavanan N, Shankaran S, Laptook AR, Carper BA, Das A, Carlo WA, Cotten CM, Duncan AF, Higgins RD; EUNICE KENNEDY SHRIVER NICHD NEONATAL RESEARCH NETWORK. Early Determination of Prognosis in Neonatal Moderate or Severe Hypoxic-Ischemic Encephalopathy. Pediatrics. 2021 Jun;147(6):e2020048678. doi: 10.1542/peds.2020-048678. Epub 2021 May 13.
• Shankaran S, Laptook AR, Pappas A, McDonald SA, Das A, Tyson JE, Poindexter BB, Schibler K, Bell EF, Heyne RJ, Pedroza C, Bara R, Van Meurs KP, Huitema CMP, Grisby C, Devaskar U, Ehrenkranz RA, Harmon HM, Chalak LF, DeMauro SB, Garg M, Hartley-McAndrew ME, Khan AM, Walsh MC, Ambalavanan N, Brumbaugh JE, Watterberg KL, Shepherd EG, Hamrick SEG, Barks J, Cotten CM, Kilbride HW, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Effect of Depth and Duration of Cooling on Death or Disability at Age 18 Months Among Neonates With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial. JAMA. 2017 Jul 4;318(1):57-67. doi: 10.1001/jama.2017.7218.
• Pedroza C, Tyson JE, Das A, Laptook A, Bell EF, Shankaran S; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Advantages of Bayesian monitoring methods in deciding whether and when to stop a clinical trial: an example of a neonatal cooling trial. Trials. 2016 Jul 22;17(1):335. doi: 10.1186/s13063-016-1480-4.
• Shankaran S, Laptook AR, Pappas A, McDonald SA, Das A, Tyson JE, Poindexter BB, Schibler K, Bell EF, Heyne RJ, Pedroza C, Bara R, Van Meurs KP, Grisby C, Huitema CM, Garg M, Ehrenkranz RA, Shepherd EG, Chalak LF, Hamrick SE, Khan AM, Reynolds AM, Laughon MM, Truog WE, Dysart KC, Carlo WA, Walsh MC, Watterberg KL, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial. JAMA. 2014 Dec 24-31;312(24):2629-39. doi: 10.1001/jama.2014.16058.
• Bonifacio SL, Chalak LF, Van Meurs KP, Laptook AR, Shankaran S. Neuroprotection for hypoxic-ischemic encephalopathy: Contributions from the neonatal research network. Semin Perinatol. 2022 Nov;46(7):151639. doi: 10.1016/j.semperi.2022.151639. Epub 2022 Jun 10.

Helpful Links

• Neonatal Research Network website

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: August 31, 2010
• First Submitted That Met QC Criteria: August 31, 2010
• First Posted (Estimate): September 1, 2010

Study Record Updates

• Last Update Posted (Actual): April 13, 2023
• Last Update Submitted That Met QC Criteria: March 21, 2023
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Hypothermia; Perinatal asphyxia; NICHD Neonatal Research Network; Hypoxic-ischemic encephalopathy (HIE); Neonatal depression; Fetal acidosis
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Central Nervous System Diseases; Nervous System Diseases; Signs and Symptoms, Respiratory; Brain Ischemia; Ischemia; Brain Diseases; Hypoxia; Hypoxia, Brain; Hypoxia-Ischemia, Brain
• Other Study ID Numbers: NICHD-NRN-0043; U10HD036790 (U.S. NIH Grant/Contract); U10HD021364 (U.S. NIH Grant/Contract); U10HD021373 (U.S. NIH Grant/Contract); U10HD021385 (U.S. NIH Grant/Contract); U10HD027851 (U.S. NIH Grant/Contract); U10HD027853 (U.S. NIH Grant/Contract); U10HD027856 (U.S. NIH Grant/Contract); U10HD027871 (U.S. NIH Grant/Contract); U10HD027880 (U.S. NIH Grant/Contract); U10HD027904 (U.S. NIH Grant/Contract); U10HD034216 (U.S. NIH Grant/Contract); U10HD040492 (U.S. NIH Grant/Contract); U10HD040689 (U.S. NIH Grant/Contract); U10HD053089 (U.S. NIH Grant/Contract); U10HD053109 (U.S. NIH Grant/Contract); U10HD053119 (U.S. NIH Grant/Contract); U10HD053124 (U.S. NIH Grant/Contract); UL1RR024139 (U.S. NIH Grant/Contract); UL1RR025744 (U.S. NIH Grant/Contract); UL1RR024979 (U.S. NIH Grant/Contract); U10HD068244 (U.S. NIH Grant/Contract); U10HD068263 (U.S. NIH Grant/Contract); U10HD068270 (U.S. NIH Grant/Contract); U10HD068278 (U.S. NIH Grant/Contract); U10HD068284 (U.S. NIH Grant/Contract); UL1RR025764 (U.S. NIH Grant/Contract); UL1RR025008 (U.S. NIH Grant/Contract); UL1RR025747 (U.S. NIH Grant/Contract); UL1RR025761 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Study Data/Documents

1. Publication